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Prolonged exposure to antigens may result in high IgG4 antibody titres as was shown in a previous paper (Aalberse et al., 1983b). In novice bee keepers, a shift in the IgGI/IgG4 ratio of the response against phospholipase-A (PLA; a major component of bee venom) occurred. This resulted in an IgG4-dominated response after approximately 2 years of bee-keeping experience. Subject of the present study was the influence of relatively high concentrations of IgG4 antibodies on the biological activity of immune complexes. In the PLA antigen model, it was demonstrated (a) that IgG4-containing immune complexes do not activate complement and (b) that lgG4 antibodies effectively inhibit immune precipitation and complement activation by IgG1 antibodies. Evidence is provided that lgG4 antibodies inhibit binding of Clq to IgG1 in mixed, IgG1- and lgG4-containing complexes. It is proposed that IgG4 antibodies protect against the biological effects of the complement-fixing IgG subclasses. For this reason, determination of the total IgG response or just determination of antibody activity in the complement-fixing isotypes is insufficient in immune-complex diseases. The modulating effect of the non-complement-fixing isotypes should be taken into account to predict the biological activity of the immune complexes. [ABSTRACT FROM AUTHOR]

Background: Clinical studies investigating medicinal products need to comply with laws concerning good clinical practice (GCP) and good manufacturing practice (GMP) to guarantee the quality and safety of the product, to protect the health of the participating individual and to assure proper performance of the study. However, there are no specific regulations or guidelines for non-Medicinal Investigational Products (non-MIPs) such as allergens, enriched food supplements, and air pollution components. As a consequence, investigators will avoid clinical research and prefer preclinical models or in vitro testing for e.g. toxicology studies.the Aim Of This Article Is To: 1) briefly review the current guidelines and regulations for Investigational Medicinal Products; 2) present a standardised approach to ensure the quality and safety of non-MIPs in human in vivo research; and 3) discuss some lessons we have learned.Methods and Results: We propose a practical line of approach to compose a clarifying product dossier (PD), comprising the description of the production process, the analysis of the raw and final product, toxicological studies, and a thorough risk-benefit-analysis. This is illustrated by an example from a human in vivo research model to study exposure to air pollutants, by challenging volunteers with a suspension of carbon nanoparticles (the component of ink cartridges for laser printers).Conclusion: With this novel risk-based approach, the members of competent authorities are provided with standardised information on the quality of the product in relation to the safety of the participants, and the scientific goal of the study. [ABSTRACT FROM AUTHOR]

To cite this article: van de Pol MA, Lutter R, van Ree R, van der Zee JS. Increase in allergen-specific IgE and ex vivo Th2 responses after a single bronchial challenge with house dust mite in allergic asthmatics. Allergy 2012; 67: 67-73. Abstract Background: Airway responsiveness to allergen in patients with allergic asthma is studied by bronchial allergen challenge. Although the typical features of the early and late responses on lung function and bronchial inflammation after allergen challenge are well known, little has been reported as yet on any changes in systemic allergic and immunologic parameters after 4-6 weeks. Methods: In a clinical study, 27 subjects with allergic asthma and house dust mite (HDM) allergy underwent a bronchial allergen challenge with HDM. Blood samples were collected before and 5 weeks after allergen challenge. Serum levels of total IgE and allergen-specific IgE were measured, and peripheral blood mononuclear cells were isolated and stimulated ex vivo with HDM to determine the allergen-specific T-cell cytokine response. Results: Five weeks after bronchial allergen challenge with HDM, the amount of circulating IgE against HDM and the major allergenic components Der p1 and Der p2 was significantly increased (10.8% and 8.8%, respectively). IgE antibodies against other environmental allergens decreased (grass pollen) or remained unchanged (cat dander). Allergen-induced Th2-cytokine production was also significantly increased ( P < 0.001, P = 0.014, and P = 0.006 for IL-4, IL-5, and IL-13, respectively). The increase in Der p1- and Der p2-specific IgE in serum correlated with increased numbers of Th2-cytokine-producing cells (Rs = 0.56, P = 0.002 and Rs = 0.54, P = 0.004 for IL-4 and IL-13, respectively). Conclusions: A single bronchial allergen challenge with HDM is accompanied by increased levels of allergen-specific IgE for HDM in serum and an enhanced Th2 response to HDM still detectable 5 weeks after challenge. [ABSTRACT FROM AUTHOR]

Background: The modified Th2 response, defined as an IgG4 response in the absence of IgE, is suggested to protect against the development of allergic sensitization. However, studies suggesting this protective effect all had a cross-sectional design, making it impossible to study the development of both responses. Aim of the study: We aimed to study the dynamics in IgG4 antibodies in relation to allergic sensitization in an occupational cohort of starting laboratory animal workers. Moreover, we studied the relation between exposure, antibody responses, atopy and self reported allergic symptoms. Methods: A total of 110 starting animal workers were followed for 2 years. IgG4 antibodies against rats and mice were assessed. Workers were tested for allergic sensitization and exposure to animal allergens was estimated. Symptom status was assessed using questionnaires. Results: Rat and mouse specific IgG4 antibodies were present before the development of allergy and did not significantly change over time. Allergic sensitization was related to exposure and atopic status but high levels of IgG4 showed no protective effect. In contrary, workers that developed mouse specific sensitization during follow up had higher levels of mouse specific IgG4. Symptoms were related to allergic sensitization and IgG4 levels did not influence that relationship. Conclusions: IgG4 antibodies are present before IgE antibodies develop and IgG4 levels are stable over time. In our occupational cohort, the modified Th2 response had no protective effect on development of sensitization or allergic symptoms. [ABSTRACT FROM AUTHOR]

Background: Previous studies suggest that pre/probiotics can be used in the prevention and treatment of early allergic disease in newborns and young children. Objective: To determine the effect of treatment with synbiotics (90% short-chain galacto-oligosaccharides, 10% long-chain fructo-oligosaccharides: Immunofortis® and Bifidobacterium breve M-16V) on allergic responses in adults with established allergic asthma. Primary outcome was allergen-induced bronchial inflammation as represented by eosinophil counts. Methods: Twenty-nine patients with asthma and house dust mite (HDM) allergy were randomized in a double-blind, parallel design to receive placebo or synbiotics for 4 weeks. At study entry and after treatment, a bronchial allergen challenge with HDM was performed, followed by lung function tests, collection of blood (in/ ex vivo IL-5) and induced sputum (inflammatory parameters). During treatment, a diary was kept with peak expiratory flow (PEF) and asthma scores. Results: Treatment did not affect the allergen-induced increase in sputum eosinophils at 6 and 24 h after challenge. Likewise, other parameters for bronchial inflammation and early and late changes in lung function did not differ upon treatment. Both the morning and evening PEF, however, significantly increased during synbiotics treatment (morning P = 0.003, evening P = 0.011). Also, the increase in serum IL-5 after allergen challenge was significantly inhibited by synbiotics (P = 0.034), as was ex vivo allergen-induced Th2-cytokine (IL-5 and IL-4+ IL-13) production by PBMCs (P = 0.046). In vivo (24 h) and ex vivo IL-5 production were associated. Conclusion: Four-week treatment with synbiotics had no effect on bronchial inflammation and LAR, but did significantly reduce systemic production of Th2-cytokines after allergen challenge and improved PEF. [ABSTRACT FROM AUTHOR]

To cite this article: Krop EJM, van de Pol MA, Lutter R, Heederik DJJ, Aalberse RC, van der Zee JS. Dynamics in cytokine responses during the development of occupational sensitization to rats. Allergy 2010; 65: 1227–1233. Background: Occupational allergy forms an attractive model to study the development of allergic responses, as in some occupations it has a high incidence and develops quickly. In a cohort of starting laboratory animal workers, we previously found 20% sensitization to animal allergens within 2 years. Methods: We compared cellular responses of incident laboratory animal workers who developed rat-specific sensitization (cases, n = 18) during 2 years of follow-up to control animal workers matched for atopic status but without sensitization after follow-up (controls, n = 18). Practically, this is a case–control study, nested within the cohort. Rat-specific IgE antibodies were measured in sera, and allergen-specific and nonspecific cytokine responses were measured in whole blood and in isolated peripheral blood mononuclear cells. Results: Self-reported allergic symptoms were related to the presence of rat-specific IgE ( P ≤ 0.01). Cases developed a rat allergen–specific interleukin (IL)-4 response during sensitization, while controls did not show an increased IL-4 response (at visit D: 33 vs 5 IL-4 producing cells/106 cells, P < 0.001). The IL-4 response was related to the levels of rat-specific IgE in cases (visit D: rho = 0.706, P < 0.001). By contrast, allergen-specific IL-10 and interferon γ (IFNγ) responses as well as nonspecific cytokine responses were comparable between cases and controls. Conclusion: This study is the first to show the development of an allergen-specific IL-4 response in adult human subjects during allergen-specific sensitization. This IL-4 response was quantitatively associated with the development of the specific IgE antibodies. Allergen-specific or nonspecific IL-10 and IFNγ responses showed no protective effect on the development of allergic sensitization. [ABSTRACT FROM AUTHOR]

The Health Council of the Netherlands published a report in which the best procedure and method for recommending health-based occupational exposure limits (OELs) for inhaled allergens were identified by evaluating the scientific state of the art. Many respiratory disorders in the workplace arise from inhalation of substances which can cause allergy. To protect workers against respiratory allergy, various preventive measures are taken, one of them being reduction of exposure by setting legally binding standards. These are based on health-based OELs that specify a level of exposure to an airborne substance, a threshold level, below which it may reasonably be expected that there is no risk of adverse health effects. The Council is of the opinion that an OEL should prevent against allergic sensitization, as sensitization plays a crucial biological role and is a prerequisite for the development of allergy. Furthermore, the Council considers it most likely that the exposure level below which no allergic sensitization develops for most allergens is so low, that OELs are difficult to set with the current knowledge and technical feasibilities. An alternative approach is to accept exposure, which carries a small predefined risk in developing allergic sensitization. In addition, it is worth considering periodic screening of exposed workers on allergic sensitization, because timely intervention can prevent worse. The feasibility of periodic screening and what else is needed to comply with the most important criteria, should however be judged case-by-case. [ABSTRACT FROM AUTHOR]

Background: Addition of the long acting β2 agonist salmeterol to inhaled corticosteroids leads to better symptomatic asthma control than increasing the dose of inhaled corticosteroids. However, little is known about the long term effects of adding salmeterol on the asthmatic inflammatory process, control of which is considered important for the long term outcome of asthma. Methods: After a 4 week fluticasone run-in period, 54 patients with allergic asthma were randomised to receive twice daily treatment with fluticasone 250 µg with or without salmeterol 50 µg for 1 year in a double blind, parallel group design (total daily dose of fluticasone 500 µin both treatment groups). Primary outcomes were sputum eosinophil numbers and eosinophil cationic protein concentrations. Secondary outcomes were neutrophil associated sputum parameters and a respiratory membrane permeability marker. The effects on allergen induced changes were determined before and at the end of the treatment period. Results: Adding salmeterol to fluticasone resulted in improved peak expiratory flow, symptom scores, rescue medication usage, and bronchial hyperresponsiveness (p<0.05 for all). There was no sustained effect on sputum cell differential counts and cytokine concentrations during the treatment period or on changes induced by allergen challenge at the end of treatment (p>0.05). However, adding salmeterol significantly reduced sputum ratios of α2-macroglobulin and albumin during the treatment period (p=0.001). Conclusions: The addition of salmeterol to fluticasone produces no sustained effect on allergen induced cellular bronchial inflammation but leads to a significant improvement in size selectivity of plasma protein permeation across the respiratory membrane. This may contribute to the improved clinical outcome seen in patients with allergic asthma when a long acting β2 agonist is combined with inhaled corticosteroids. [ABSTRACT FROM AUTHOR]

Background: Production of both antigen-specific immunoglobulin (Ig)E and IgG4 antibodies is dependent on stimulation of B cells by T helper 2 cell-derived cytokines. However, there is controversy as to their interaction. In this study, we investigated the interdependency of IgE and IgG4 antibody responses to a relatively high range of airway exposure to animal-derived proteins in an occupational setting. Moreover, associations with self-reported airway symptoms and bronchial hyperresponsiveness were established. Methods: In a cross-sectional design, employees of an animal plasma spray-drying factory were questioned about airway symptoms, exposure was measured with personal sampling technique, and serology was performed. In a selection of subjects from this population, serology was repeated 15 months later, and bronchial hyperresponsiveness was measured. Results: IgE and IgG4 antibodies were detected in 17 and 57% of all employees and were both associated with degree of exposure. Only IgE antibodies showed an independent association with self-reported airway symptoms and bronchial hyperresponsiveness. The presence of IgE antibodies was limited to employees with high levels of IgG4. Employees with IgE and symptoms appeared to have less IgG4 than asymptomatic IgE-positive individuals. The level of specific IgG4 antibodies was stable over a 15-month period. Conclusions: In high-range airway exposure, development of IgE and IgG4 antibodies depended on the level of exposure. The threshold for development of IgG4 antibodies appeared to be less than that for IgE antibodies, and IgG4 antibodies may protect against the development of symptoms. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Nitric oxide in exhaled air (eNO) is elevated in allergic asthma compared with healthy subjects and has been proposed as a marker of bronchial inflammation. However, eNO is elevated to a lesser extent in allergic non-asthmatic rhinitis as well. Considering the distinctive clinical appearances of both allergic diseases, differences in eNO are expected to persist after allergen exposure. The aim of the study was to compare allergen-induced changes in eNO in house dust mite sensitized patients with asthma and patients with perennial rhinitis without asthma symptoms. Methods: Bronchial allergen challenge was performed in 52 patients sensitized to house dust mite (Dermatophagoides pteronyssinus ), of whom 26 had non-asthmatic rhinitis and 26 had asthma. Levels of eNO were measured before and 1 h, 1 day and 1 week after challenge. Results: At baseline eNO was significantly lower in non-asthmatic rhinitis compared with asthma (geometric mean eNO (SEM): 121 (1.1) in non-asthmatic rhinitis vs 197 (1.1) nl/min in asthma, P < 0.006). However, the increase in eNO after bronchial allergen challenge in non-asthmatic rhinitis, in particular in those patients with a dual asthmatic response, significantly exceeded the increase in asthma resulting in similar levels of eNO after challenge (geometric mean eNO (SEM) at 24 h postchallenge 204 (1.1) in non-asthmatic rhinitis vs 244 (1.1)nl/min in asthma, P = 0.3). Conclusion: The difference in eNO between non-asthmatic rhinitis and asthma at baseline is abolished after allergen exposure due to a significantly greater increase in eNO in non-asthmatic rhinitis. [ABSTRACT FROM AUTHOR]

Summary Background It is presently unknown which factors determine the occurrence and persistence of asthma in house dust mite-allergic individuals. The level of allergen-specific IgE antibodies does not seem to be decisive for asthmatic symptoms. Moreover, levels of exposure to mite allergens do not seem to differ significantly between asthmatic and non-asthmatics individuals. Aim It was hypothesized that the presence or absence of asthmatic symptoms in house dust mite-allergic patients is associated with quantitative or qualitative differences in the cellular bronchial inflammatory response during the late phase of the allergic reaction. This hypothesis was tested in the bronchial allergen challenge model. Material and methods Whole lung challenges with house dust mite extract were performed in 52 house dust mite-allergic subjects, of whom 26 had asthma and 26 had perennial rhinitis without asthmatic symptoms. Primary outcomes were parameters for bronchial inflammation in serial samples of induced sputum (cell differentials, eosinophil cationic protein (ECP), interleukin-8 (IL-8), myeloperoxydase (MPO)). In addition, lung function, non-specific bronchial hyper- responsiveness and serial blood samples (eosinophils and IL-5) were analysed. Results At baseline sputum eosinophils and ECP were similar in both groups but neutrophils and IL-8 were higher in asthmatics. The early bronchoconstriction after allergen challenge was similar in asthma and non-asthmatic rhinitis (median decrease in FEV1: asthma - 31.7% vs. non-asthmatics - 29.1%, P > 0.1). The late phase bronchoconstriction was significantly greater in asthma (median decrease in FEV1: asthma - 27.6% vs. non-asthmatics - 18.9%, P = 0.02). Induction of bronchial hyper-responsiveness was similar in both groups. Bronchial allergen challenge elicited significant increases in sputum eosinophils and ECP, which were indistinguishable for both groups (P > 0.1 and P = 0.07, respectively). In... [ABSTRACT FROM AUTHOR]

IL-13 is strongly implicated in the development of asthma and chronic obstructive polymonary disease (COPD). We previously identified an IL-13 promoter polymorphism (-1055 C to T) that is associated with allergic asthma. We now report an increased frequency of the -1055 T allele in COPD patients compared to healthy controls (P = 0.002) and compared to a second control group consisting of smoking individuals with normal lung function (P = 0.01). A closely linked IL-13 exon polymorphism is present at normal allelic frequencies (P = 0.3 and 0.4, respectively). In addition, we observed a normal distribution of two IL-4 polymorphisms at positions -590 and +33 (P = 0.2 and 0.9, respectively). These results could implicate a functional role for the IL-13 promoter polymorphism in the enhanced risk to develop COPD. [ABSTRACT FROM AUTHOR]

Background: Although it has been repeatedly suggested that chronic obstructive pulmonary disease (COPD) is associated with depression, no conclusion has so far been reached. A study was undertaken to investigate whether depression occurs more often in patients with COPD than in controls. The demographic and clinical variables associated with depression were also determined.Methods: Patients with a registered diagnosis of obstructive airway disease in general practice, aged > or=40 years, forced expiratory volume in 1 second (FEV(1)) <80% predicted, FEV(1) reversibility Results: In patients with severe COPD (FEV(1) <50% predicted), the prevalence of depression was 25.0% compared with 17.5% in controls and 19.6% in patients with mild to moderate COPD. When the results were adjusted for demographic variables and comorbidity, the risk for depression was 2.5 times greater for patients with severe COPD than for controls (OR 2.5, 95% CI 1.2 to 5.4). In patients with mild to moderate COPD this increased risk of depression was not seen. Living alone, reversibility of FEV(1) % predicted, respiratory symptoms and physical impairment were significantly associated with the scores on the CES-D scale.Conclusion: Patients with severe COPD are at increased risk of developing depression. The results of this study underscore the importance of reducing symptoms and improving physical functioning in patients with COPD. [ABSTRACT FROM AUTHOR]

Background: The models for exposure to house dust in research and clinical practice are selected with respect to their role in IgE-mediated immediate hypersensitivity. The use of isolated major allergens instead of complex allergen extracts is becoming increasingly popular as it offers some important advantages for quantitative measures in diagnosis and research. Objective: To compare house dust mite extract and isolated mite major allergens with respect to their ability to induce early and late asthmatic responses and bronchial hyperreactivity. Methods: Bronchial responses to house dust mite (HDM, Dermatophagoides pteronyssinus) extract and isolated major allergens from HDM (Der p 1 and Der p 2) were compared in a double-blind, randomized, cross-over study in 20 patients with mild to moderate asthma who were allergic to HDM. Allergen was titrated to a standardized early asthmatic response. Bronchial hyper-responsiveness to histamine (PC[sub 20]histamine) was determined before and after allergen inhalation to assess allergen-induced bronchial hyper-responsiveness and IL-5 was measured in serum. In addition, the allergens were applied in intracutaneous skin tests and activation of basophil leucocytes and proliferation of peripheral blood mononuclear cells was tested in vitro. Results: After a similar early asthmatic response (mean Δforced expiratory volume in 1 s (FEV[sub 1])[sub ,max] -29.4 (SD 7.2) vs. -33.1 (8.6) %; mean difference 3.6 (95% CI -0.9 to 8.2) %), the late asthmatic response (mean ΔFEV[sub 1,max] -45.9 (21.9) vs. -32.7 (22.3) %; mean difference 13.2 (3.8–22.3) %), the degree of allergen-induced bronchial hyper-responsiveness (mean ΔPC[sub 20]histamine, 1.8 (1.0) vs. 1.2 (0.9) doubling dose; mean difference 0.6 (0.2–1.1) doubling dose) and serum IL-5 at 6 h were found to be significantly higher after bronchial challenge with HDM extract than after challenge with an isolated HDM major allergen. Likewise, there was ... [ABSTRACT FROM AUTHOR]

Background: IgE-dependent histamine-releasing factor (HRF) can distinguish between IgE+ and IgE-. In contrast to IgE-, IgE+ sensitizes basophils to release histamine in response to HRF. But we do not know what particular feature distinguishes IgE+ from IgE-. The objective was to investigate the hypothesis that IgE+ is polymeric IgE. Methods: IgE+ plasma was separated by size-exclusion chromatography. The basophil-sensitizing capacity of the fractions was analyzed in response to HRF produced by mononuclear cells. Results: We showed that monomeric IgE sensitized basophils to release histamine in response to HRF and to house-dust mite, whereas no enhanced reactivity was found in the fractions containing polymeric IgE. Conclusions: HRF reacts with monomeric IgE, and not (exclusively) with polymeric IgE. [ABSTRACT FROM AUTHOR]

IL-13 plays a crucial role in the development of allergic asthma by several mechanisms, including induction of IgE antibodies, airway eosinophilia and hyper-reactivity. We previously established a deregulated production of IL-13 by T cells from allergic asthma patients. In this report we describe the identification of a novel IL-13 promoter polymorphism (C to T exchange) at position -1055. The IL-13 -1055 TT genotype is associated with allergic asthma (P = 0.002), altered regulation of IL-13 production (P < 0.002), and increased binding of nuclear proteins to this region. We postulate that the presence of this polymorphism predisposes to the development of allergic asthma. [ABSTRACT FROM AUTHOR]

A response by E. J. Krop and colleagues to a letter to the editor about their article "IgG4 antibodies against rodents in laboratory animal workers do not protect against allergic sensitization" in the 2011 issue is presented.

Summary Background In children at high risk of inhalation allergy, food sensitization is associated with an increased risk for sensitization to inhalant allergens. Furthermore, this association was also found in a cross-sectional study. Objective To examine in a prospective study, whether levels of IgG to foods (i.e. mixture of wheat and rice, mixture of soy bean and peanut, egg white, cow's milk, meat, orange and potato) indicate an increased risk for the future development of IgE antibodies to inhalant allergens in a low-risk population and whether they can be used as predictors of the subsequent development of IgE antibodies in young, initially IgE-negative children. Methods Coughing children, aged 1–5, visiting their GPs, were tested for IgE antibodies to mite, dog and cat (RAST) and IgG (ELISA) to foods. All IgE-negative children were retested for IgE antibodies after two years. The IgG results (66 percentiles) of the first blood sample were compared to the RAST-scores of the second blood sample. Results After two years, 51 out of 397 (12.8%) originally IgE-negative children, had become IgE-positive for cat, dog and/or mite. An increased IgG antibody level to wheat-rice (OR = 2.2) and to orange (OR = 2.0) indicated an increased risk of developing IgE to cat, dog or mite allergens. In addition to IgG to a mixture of wheat-rice and orange; total IgE, breastfeeding, eczema as a baby and age were the most important predictors for the subsequent development of IgE to inhalant allergens. Discussion An increased IgG antibody level to a mixture of wheat-rice or orange, indicates an increased risk of developing IgE to cat, dog or mite allergens. This indicates that excessive activity of the mucosal immune system is present before IgE antibodies to airborne allergens can be demonstrated. Nevertheless, IgG to foods is not very helpful (with a positive predictive value of 16.5%, and negative predictive value of 90.6%) in identifying individual children at risk... [ABSTRACT FROM AUTHOR]